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Conditioning Regimens

High fludarabine exposure and relationship with treatment-related mortality after nonmyeloablative hematopoietic cell transplantation

Bone Marrow Transplantation volume 46, pages 20–26 (2011)Cite this article

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Abstract

Despite its common use in nonmyeloablative preparative regimens, the pharmacokinetics of fludarabine are poorly characterized in hematopoietic cell transplantation (HCT) recipients and exposure-response relationships remain undefined. The objective of this study was to evaluate the association between plasma F-ara-A exposure, the systemically circulating moiety of fludarabine, and engraftment, acute GVHD, TRM and OS after HCT. The preparative regimen consisted of CY 50 mg/kg/day i.v. day –6; plus fludarabine 30–40 mg/m2/day i.v. on days –6 to –2 and TBI 200 cGy on day –1. F-ara-A pharmacokinetics were carried out with the first dose of fludarabine in 87 adult patients. Median (range) F-ara-A area-under-the-curve (AUC(0−∞)) was 5.0 μg h/mL (2.0–11.0), clearance 15.3 L/h (6.2–36.6), Cmin 55 ng/mL (17–166) and concentration on dayzero 16.0 ng/mL (0.1–144.1). Despite dose reductions, patients with renal insufficiency had higher F-ara-A exposures. There was strong association between high plasma concentrations of F-ara-A and increased risk of TRM and reduced OS. Patients with an AUC(0−∞) greater than 6.5 μg h/mL had 4.56 greater risk of TRM and significantly lower OS. These data suggest that clinical strategies are needed to optimize dosing of fludarabine to prevent overexposure and toxicity in HCT.

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Acknowledgements

The technical assistance of Jim Fisher and Jason Dagit is gratefully acknowledged. We also acknowledge the work and dedication of our study nurse coordinator, Dixie Lewis. This work was supported by grants from the National Institutes of Health, National Cancer Institute (CA096622) (PJ), and National Institutes of Health National Center for Research Services (M01-RR00400).

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Authors and Affiliations

  1. Department of Experimental and Clinical Pharmacology, University of Minnesota, Minneapolis, MN, USA

    J R Long-Boyle & P A Jacobson

  2. Department of Pharmacy, University of Minnesota Medical Center, Fairview, Minneapolis, MN, USA

    J R Long-Boyle, K G Green & J Rogosheske

  3. Division of Hematology, Oncology, Transplantation, University of Minnesota, Minneapolis, MN, USA

    C G Brunstein, D J Weisdorf, J S Miller, J E Wagner & P B McGlave

  4. Biostatistic Core, Masonic Cancer Center, University of Minnesota, Minneapolis, MN, USA

    Q Cao

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Correspondence to P A Jacobson.

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Long-Boyle, J., Green, K., Brunstein, C. et al. High fludarabine exposure and relationship with treatment-related mortality after nonmyeloablative hematopoietic cell transplantation. Bone Marrow Transplant 46, 20–26 (2011). https://doi.org/10.1038/bmt.2010.53

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